Category Archives: Dolor

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Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies.

Category : Dolor

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Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies.

Br J Pain. 2017 Aug;11(3):119-133

Authors: Fallon MT, Albert Lux E, McQuade R, Rossetti S, Sanchez R, Sun W, Wright S, Lichtman AH, Kornyeyeva E

Abstract
BACKGROUND: Opioids are critical for managing cancer pain, but may provide inadequate relief and/or unacceptable side effects in some cases.
OBJECTIVE: To assess the analgesic efficacy of adjunctive Sativex (Δ(9)-tetrahydrocannabinol (27 mg/mL): cannabidiol (25 mg/mL)) in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy.
METHODS: This report describes two phase 3, double-blind, randomized, placebo-controlled trials. Eligible patients had advanced cancer and average pain numerical rating scale (NRS) scores ≥4 and ≤8 at baseline, despite optimized opioid therapy. In Study-1, patients were randomized to Sativex or placebo, and then self-titrated study medications over a 2-week period per effect and tolerability, followed by a 3-week treatment period. In Study-2, all patients self-titrated Sativex over a 2-week period. Patients with a ≥15% improvement from baseline in pain score were then randomized 1:1 to Sativex or placebo, followed by 5-week treatment period (randomized withdrawal design).
RESULTS: The primary efficacy endpoint (percent improvement (Study-1) and mean change (Study-2) in average daily pain NRS scores) was not met in either study. Post hoc analyses of the primary endpoints identified statistically favourable treatment effect for Sativex in US patients <65 years (median treatment difference: 8.8; 95% confidence interval (CI): 0.00-17.95; p = 0.040) that was not observed in patients <65 years from the rest of the world (median treatment difference: 0.2; 95% CI: -5.00 to 7.74; p = 0.794). Treatment effect in favour of Sativex was observed on quality-of-life questionnaires, despite the fact that similar effects were not observed on NRS score. The safety profile of Sativex was consistent with earlier studies, and no evidence of abuse or misuse was identified.
CONCLUSIONS: Sativex did not demonstrate superiority to placebo in reducing self-reported pain NRS scores in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy, although further exploration of differences between United States and patients from the rest of the world is warranted.

PMID: 28785408 [PubMed]

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Sleep disturbances and severe stress as glial activators: key targets for treating central sensitization in chronic pain patients?

Category : Dolor

Sleep disturbances and severe stress as glial activators: key targets for treating central sensitization in chronic pain patients?

Expert Opin Ther Targets. 2017 Jul 07;:

Authors: Nijs J, Loggia ML, Polli A, Moens M, Huysmans E, Goudman L, Meeus M, Vanderweeën L, Ickmans K, Clauw D

Abstract
INTRODUCTION: The mechanism of sensitization of the central nervous system partly explains the chronic pain experience in many patients, but the etiological mechanisms of this central nervous system dysfunction are poorly understood. Recently, an increasing number of studies suggest that aberrant glial activation takes part in the establishment and/or maintenance of central sensitization. Areas covered: This review focused on preclinical work and mostly on the neurobiochemistry studied in animals, with limited human studies available. Glial overactivation results in a low-grade neuroinflammatory state, characterized by high levels of BDNF, IL-1β, TNF-α, which in turn increases the excitability of the central nervous system neurons through mechanisms like long-term potentiation and increased synaptic efficiency. Aberrant glial activity in chronic pain might have been triggered by severe stress exposure, and/or sleeping disturbances, each of which are established initiating factors for chronic pain development. Expert opinion: Potential treatment avenues include several pharmacological options for diminishing glial activity, as well as conservative interventions like sleep management, stress management and exercise therapy. Pharmacological options include propentofylline, minocycline, β -adrenergic receptor antagonists, and cannabidiol. Before translating these findings from basic science to clinical settings, more human studies exploring the outlined mechanisms in chronic pain patients are needed.

PMID: 28685641 [PubMed – as supplied by publisher]

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Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats.

Category : Dolor

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Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats.

Front Pharmacol. 2017;8:391

Authors: Genaro K, Fabris D, Arantes ALF, Zuardi AW, Crippa JAS, Prado WA

Abstract
Background: Pain involves different brain regions and is critically determined by emotional processing. Among other areas, the rostral anterior cingulate cortex (rACC) is implicated in the processing of affective pain. Drugs that interfere with the endocannabinoid system are alternatives for the management of clinical pain. Cannabidiol (CBD), a phytocannabinoid found in Cannabis sativa, has been utilized in preclinical and clinical studies for the treatment of pain. Herein, we evaluate the effects of CBD, injected either systemically or locally into the rACC, on mechanical allodynia in a postoperative pain model and on the negative reinforcement produced by relief of spontaneous incision pain. Additionally, we explored whether CBD underlies the reward of pain relief after systemic or rACC injection. Methods and Results: Male Wistar rats were submitted to a model of incision pain. All rats had mechanical allodynia, which was less intense after intraperitoneal CBD (3 and 10 mg/kg). Conditioned place preference (CPP) paradigm was used to assess negative reinforcement. Intraperitoneal CBD (1 and 3 mg/kg) inverted the CPP produced by peripheral nerve block even at doses that do not change mechanical allodynia. CBD (10 to 40 nmol/0.25 μL) injected into the rACC reduced mechanical allodynia in a dose-dependent manner. CBD (5 nmol/0.25 μL) did not change mechanical allodynia, but reduced peripheral nerve block-induced CPP, and the higher doses inverted the CPP. Additionally, CBD injected systemically or into the rACC at doses that did not change the incision pain evoked by mechanical stimulation significantly produced CPP by itself. Therefore, a non-rewarding dose of CBD in sham-incised rats becomes rewarding in incised rats, presumably because of pain relief or reduction of pain aversiveness. Conclusion: The study provides evidence that CBD influences different dimensions of the response of rats to a surgical incision, and the results establish the rACC as a brain area from which CBD evokes antinociceptive effects in a manner similar to the systemic administration of CBD. In addition, the study gives further support to the notion that the sensorial and affective dimensions of pain may be differentially modulated by CBD.

PMID: 28680401 [PubMed – in process]

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Single and combined effects of delta(9) -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain.

Category : Dolor

Single and combined effects of delta(9) -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain.

Br J Pharmacol. 2017 May 26;:

Authors: King KM, Myers AM, Soroka-Monzo AJ, Tuma RF, Tallarida RJ, Walker EA, Ward SJ

Abstract
BACKGROUND AND PURPOSE: It has been suggested that the non-psychoactive phytocannabinoid cannabidiol (CBD) can impact the pharmacological effects of delta-9-tetrahydrocannabinol (THC). We tested the hypothesis that CBD and THC would significantly mitigate mechanical sensitivity in a mouse model of paclitaxel-induced neuropathic pain, and that CBD+THC combinations would produce synergistic effects. We also tested the hypothesis that CBD would attenuate oxaliplatin- and vincristine- induced mechanical sensitivity.
EXPERIMENTAL APPROACH: Paclitaxel-treated mice (8.0 mg/kg IP, days 1, 3, 5 and 7) were pretreated with CBD (0.625 – 20.0 mg/kg IP), THC (0.625 – 20.0 mg/kg IP) or CBD+THC (0.04+0.04 – 20.0+20.0 mg/kg IP) and mechanical sensitivity was assessed on days 9, 14, and 21. Oxaliplatin-treated (6.0 mg/kg IP, day 1) or vincristine-treated mice (0.1 mg/kg IP days 1-7) were pretreated with CBD (1.25 – 10.0 mg/kg IP), THC (10.0 mg/kg IP), or THC+CBD (0.16 mg/kg THC + 0.16 mg/kg CBD IP).
KEY RESULTS: Both CBD and THC alone attenuated mechanical allodynia in mice treated with paclitaxel. Very low ineffective doses of CBD and THC were synergistic when given in combination. CBD also attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity, while THC significantly attenuated vincristine- but not oxaliplatin-induced mechanical sensitivity. The low dose combination significantly attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity.
CONCLUSIONS AND IMPLICATIONS: CBD may be potent and effective at preventing the development of CIPN, and its clinical utility may be enhanced by co-administration of low doses of THC. These treatment strategies would increase the therapeutic window of Cannabis-based pharmacotherapies.

PMID: 28548225 [PubMed – as supplied by publisher]

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Short-Term Efficacy of CBD-Enriched Hemp Oil in Girls with Dysautonomic Syndrome after Human Papillomavirus Vaccination.

Category : Dolor

Short-Term Efficacy of CBD-Enriched Hemp Oil in Girls with Dysautonomic Syndrome after Human Papillomavirus Vaccination.

Isr Med Assoc J. 2017 Feb;19(2):79-84

Authors: Palmieri B, Laurino C, Vadalà M

Abstract
BACKGROUND: Cannabidiol (CBD)-based treatments for several diseases, including Tourette’s syndrome, multiple sclerosis, epilepsy, movement disorders and glaucoma, are proving to be beneficial and the scientific clinical background of the drug is continuously evolving.
OBJECTIVES: To investigate the short-term effect of CBD-enriched hemp oil for relieving symptoms and improving the life quality (QOL) in young girls with adverse drug effects (ADRs) following human papillomavirus (HPV) vaccine.
METHODS: In this anecdotal, retrospective, “compassionate-use”, observational, open-label study, 12 females (age 12-24 years) with severe somatoform and dysautonomic syndrome following HPV vaccination were given sublingual CBD-rich hemp oil drops, 25 mg/kg per day supplemented by 2-5 mg/ml CBD once a week until a maximum dose of 150 mg/ml CBD per day was reached over a 3 month period. Patients’ quality of life was evaluated using the medical outcome short-form health survey questionnaire (SF-36).
RESULTS: Two patients dropped out due to iatrogenic adverse events and another two patients stopped the treatment early due to lack of any improvement. SF-36 showed significant benefits in the physical component score (P < 0.02), vitality (P < 0.03) and social role functioning (P < 0.02) after the treatment. The administration of hemp oil also significantly reduced body pain according to the SF-36 assessment. No significant differences from the start of treatment to several months post-treatment were detected in role limitations due to emotional reactions (P = 0.02).
CONCLUSIONS: This study demonstrated the safety and tolerability of CBD-rich hemp oil and the primary efficacy endpoint. Randomized controlled trials are warranted to characterize the safety profile and efficacy of this compound.

PMID: 28457055 [PubMed – in process]

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Cannabidiol-Δ(9)-tetrahydrocannabinol interactions on acute pain and locomotor activity.

Category : Dolor

Cannabidiol-Δ(9)-tetrahydrocannabinol interactions on acute pain and locomotor activity.

Drug Alcohol Depend. 2017 Apr 15;175:187-197

Authors: Britch SC, Wiley JL, Yu Z, Clowers BH, Craft RM

Abstract
BACKGROUND: Previous studies suggest that cannabidiol (CBD) may potentiate or antagonize Δ(9)-tetrahydrocannabinol’s (THC) effects. The current study examined sex differences in CBD modulation of THC-induced antinociception, hypolocomotion, and metabolism.
METHODS: In Experiment 1, CBD (0, 10 or 30mg/kg) was administered 15min before THC (0, 1.8, 3.2, 5.6 or 10mg/kg), and rats were tested for antinociception and locomotion 15-360min post-THC injection. In Experiments 2 and 3, CBD (30mg/kg) was administered 13h or 15min before THC (1.8mg/kg); rats were tested for antinociception and locomotion 30-480min post-THC injection (Experiment 2), or serum samples were taken 30-360min post-THC injection to examine CBD modulation of THC metabolism (Experiment 3).
RESULTS: In Experiment 1, CBD alone produced no antinociceptive effects, while enhancing THC-induced paw pressure but not tail withdrawal antinociception 4-6h post-THC injection. CBD alone increased locomotor activity at 6h post-injection, but enhanced THC-induced hypolocomotion 4-6h post-THC injection, at lower THC doses. There were no sex differences in CBD-THC interactions. In Experiments 2 and 3, CBD did not significantly enhance THC’s effects when CBD was administered 13h or 15min before THC; however, CBD inhibited THC metabolism, and this effect was greater in females than males.
CONCLUSIONS: These results suggest that CBD may enhance THC’s antinociceptive and hypolocomotive effects, primarily prolonging THC’s duration of action; however, these effects were small and inconsistent across experiments. CBD inhibition of THC metabolism as well other mechanisms likely contribute to CBD-THC interactions on behavior.

PMID: 28445853 [PubMed – as supplied by publisher]

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Neuropsychiatric and general interactions of natural and synthetic cannabinoids with drugs of abuse and medicines.

Category : Dolor

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Neuropsychiatric and general interactions of natural and synthetic cannabinoids with drugs of abuse and medicines.

CNS Neurol Disord Drug Targets. 2017 Apr 13;:

Authors: Arellano AL, Papaseit E, Romaguera A, Torrens M, Farré M

Abstract
Cannabis is the most widely used illicit drug. The two most important natural cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The THC content of cannabis has been increasing during the last years and recently appeared in the market a series of synthetic cannabinoids with potent agonist activity. Recreational users frequently combine cannabis with other drugs of abuse as alcohol, amphetamines and derivatives, nicotine and cocaine. In addition these subjects can be taking medicines for acute and chronic medical conditions. The increasing use of medicinal cannabis for chronic pain and neurological and psychiatric disorders can produce potential interactions with medications used for the symptomatic treatment of these or other diseases. THC and CBD are metabolized mainly in the liver by cytochrome P-450 isoenzymes (mainly CYP2Cs and CYP3A4). In vitro studies indicate that THC and CBD both inhibit CYP1A1, 1A2 and 1B1 enzymes, and recent studies have indicated that CBD is also a potent inhibitor of CYP2C19 and CYP3A4. Both cannabinoids may interact with other medications metabolized by the same pathway or by inducers/inhibitors of the isoenzymes. Cannabis produces sedation, impairs psychomotor performance, and increases blood pressure and heart rate. Pharmacodynamics interactions with other sedatives can potentiate the central effects but can be decreased by psychostimulants. This review focuses on the interactions between cannabinoids and alcohol, other drugs of abuse, and prescription medicines.

PMID: 28412920 [PubMed – as supplied by publisher]

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Cannabis, Cannabinoids, and Sleep: a Review of the Literature.

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Cannabis, Cannabinoids, and Sleep: a Review of the Literature.

Curr Psychiatry Rep. 2017 Apr;19(4):23

Authors: Babson KA, Sottile J, Morabito D

Abstract
PURPOSE OF REVIEW: The current review aims to summarize the state of research on cannabis and sleep up to 2014 and to review in detail the literature on cannabis and specific sleep disorders from 2014 to the time of publication.
RECENT FINDINGS: Preliminary research into cannabis and insomnia suggests that cannabidiol (CBD) may have therapeutic potential for the treatment of insomnia. Delta-9 tetrahydrocannabinol (THC) may decrease sleep latency but could impair sleep quality long-term. Novel studies investigating cannabinoids and obstructive sleep apnea suggest that synthetic cannabinoids such as nabilone and dronabinol may have short-term benefit for sleep apnea due to their modulatory effects on serotonin-mediated apneas. CBD may hold promise for REM sleep behavior disorder and excessive daytime sleepiness, while nabilone may reduce nightmares associated with PTSD and may improve sleep among patients with chronic pain. Research on cannabis and sleep is in its infancy and has yielded mixed results. Additional controlled and longitudinal research is critical to advance our understanding of research and clinical implications.

PMID: 28349316 [PubMed – in process]

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Cannabis in Chinese Medicine: Are Some Traditional Indications Referenced in Ancient Literature Related to Cannabinoids?

Category : Dolor

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Cannabis in Chinese Medicine: Are Some Traditional Indications Referenced in Ancient Literature Related to Cannabinoids?

Front Pharmacol. 2017;8:108

Authors: Brand EJ, Zhao Z

Abstract
Cannabis sativa L. (Cannabaceae) has a long history of utilization as a fiber and seed crop in China, and its achenes (“seeds”) as well as other plant parts have been recorded in Chinese medical texts for nearly 2000 years. While the primary applications of cannabis in Chinese medicine center around the use of the achenes, ancient indications for the female inflorescence, and other plant parts include conditions such as pain and mental illness that are the subject of current research into cannabinoids such as cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC). However, little previous research has been conducted to analyze the Chinese medical literature in light of recent advances in the pharmacology and taxonomy of cannabis, and most of the relevant Chinese historical records have not yet been translated into Western languages to facilitate textual research. Furthermore, many key questions remain unresolved in the Chinese literature, including how various traditional drug names precisely correspond to different plant parts, as well as the implications of long-term selection for fiber-rich cultivars on the medical applications of cannabis in Chinese medicine. In this article, prominent historical applications of cannabis in Chinese medicine are chronologically reviewed, and indications found in ancient Chinese literature that may relate to cannabinoids such as CBD and Δ(9)-THC are investigated.

PMID: 28344554 [PubMed – in process]

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